IL-30 Knockout as a Novel Therapeutic Strategy for Metastatic Prostate Cancer

Prostate cancer (PC) is the second-leading cause of cancer death in men worldwide, with approx. 1 in 44 men expected to die of the disease (source: American Cancer Society).

Previous studies identified interleukin 30 (IL-30) as a driver of PC progression and its potential as a therapeutic target for metastatic disease has received attention.

To investigate the impact of IL-30 suppression on PC metastasis, researchers at University of Chieti-Pescara and University of Rome developed a CRISPR-Cas9-based approach to delete the human IL-30 gene and examined the consequences in vitro and in in vivo.

Using lipid nanoparticles loaded with CRISPR-Cas9 and gRNA targeting the human IL-30 gene, the team observed efficient gene knockout in vivo (in xenograft models of lung metastasis) and in vitro (using 2-Organ-on-Chip models). The nanoparticles were functionalised with antibodies specific for prostate stem cell antigen (PSCA), which is known to promote the growth and metastasis of PC, and which is also highly expressed in non-small cell lung carcinoma and several other cancers (reviewed in 1).

Following intravenous injection in mice, the functionalised nanoparticles demonstrated circulation stability and efficient editing of the IL-30 gene and suppressed lung metastasis in mice bearing circulating PC cells and micro-emboli, without serious off-target effects or organ toxicity for the duration of the study.

In vitro experiments revealed that IL-30 knockout inhibited PC cell proliferation as well as expression of IL-30 and other known metastasis drivers, while the expression of the tumour suppressor gene CDH1 was elevated.

The researchers propose a patient-tailored nanoplatform for selective IL-30 gene knockout as a clinically-relevant and promising tool against PC progression. The findings were published a few days ago in Molecular Therapy (2).

References

1. Nayerpour Dizaj T, Doustmihan A, Sadeghzadeh Oskouei B, et al. Significance of PSCA as a novel prognostic marker and therapeutic target for cancer. Cancer Cell Int. 2024 Apr 16;24(1):135. doi: 10.1186/s12935-024-03320-6.
2. Cristiano Fieni, Stefania Livia Ciummo, Carlo Sorrentino, et al. Prevention of Prostate Cancer Metastasis by a CRISPR-delivering Nanoplatform for Interleukin-30 Genome Editing. Molecular Therapy 2024. doi: 10.1016/j.ymthe.2024.09.011.